DESCRIPTION (from the application): Osteoarthritis (OA) of the knee is the most common cause of chronic disability in this country and has enormous socio-economic impact. Notably, management of OA today is limited to symptomatic therapy. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most popular agents used to treat OA but elderly women, in whom OA is especially common, are at greatest risk of developing serious side effects from NSAIDs. Notablly, however, several drugs have been shown to prevent, or slow progression of, cartilage damage in animal models of 0A, and drugs are currently being developed to inhibit protease-induced cartilage damage, with a view to their use in OA. We have shown that prophylactic oral administration of doxycycline (doxy) markedly reduces the severity of cartilage damage in a canine model of OA; even when therapy was initiated after cartilage lesions were established, a protective effect was apparent. Similar results have been noted in guinea pig and rabbit models of OA. The effect is associated with reduction in the levels of collagenase and gelatinase in the OA cartilage. Based on the encouraging data in animal models of OA, we propose to conduct a multi-center, double-blind, placebo-controlled clinical trial of doxy in subjects with OA. It is our hypothesis that doxy will decrease the severity, or rate of progression, of OA. Because a disease-modifying drug for OA will, presumably, be more likely to show an effect in the early stages of the disease than when OA pathology is more advanced, our study population will be 2 obese females, 45-60 years old, with x-ray evidence of unilateral tibiofemoral OA in whom x-ray changes have been reported to develop in the contralateral knee in nearly 50% within 2 years. Subjects (n=432) will be randomized to receive doxy, 100 mg bid, or placebo for 2-1/2 years. No attempt will be made to influence NSAID and/or analgesic treatment or other measures prescribed in the course of routine clinical care. Several strategies will be employed to maximize compliance with the study medications and retention of subjects in the study, including a "faintness-of-heart" test, which will be used at the outset to eliminate noncompliers, and use of a computerized medicine cap to provide information concerning compliance with the prescribed dosing regimen between visits, permitting study personnel to aim their efforts to enhance compliance at those subjects who can best benefit from them. Our primary outcome variables will be the rate joint space narrowing (JSN, measured by a computerized system on a digitized AP radiograph of the semi-flexed knee taken with a technique to markedly reduce variability in radioanatomic positioning) and the severity of individual radiographic features of OA, e.g., osteophytes, in the contralateral knee. Because the rate of JSN in the contralateral knee is uncertain, whereas published data indicate that in knees which exhibit bony changes of OA (e.g., osteophytes) it is sufficiently rapid to permit detection of a reasonable drug effect during the study period, radiographic progression in the index knee will also serve as a primary outcome variable. In addition, we will examine changes in an algofunctional index (WOMAC), global arthritis activity, general health status (SF-36). and utilization of health services in the two treatment groups. This study should answer the question whether oral treatment with doxy - a relatively safe, readily available and inexpensive drug with which decades of clinical experience have accrued - can modify the natural history of OA in humans.